Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the Medical University of South Carolina (MUSC) is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (13/13) to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 500 9-10 year olds enriched for high-risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 1 hubs across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. MUSC's Research Project specifically focuses on structural connectivity, sex/gender effects, and neurocognitive and behavioral outcomes. This work will uncover the role of frontolimbic structural connectivity as a risk factor for and a consequence of substance use during adolescent brain development while elucidating the moderating role of sex/gender on these associations. The relationship between structural connectivity and neurocognitive and behavioral functioning before and after repeated substance use will also be examined. It is crucial that we understand the effect of adolescent substance use on the male and female brain, particularly in the developing frontolimbic regions involved in sensation seeking, impulsivity, and risk-taking, to help guide and inform adolescent drug and alcohol prevention and treatment practices and policies.